Effect of oxaliplatin-based chemotherapy on chemosensitivity in patients with peritoneal metastasis from colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: proof-of-concept study.

BACKGROUND: Chemosensitivity testing, including collagen gel droplet-embedded culture drug sensitivity test, has proven to be a useful tool in therapeutic decision-making. This retrospective analysis investigated chemosensitivity testing of peritoneal metastases collected during cytoreductive surgery (CRS), and its impact on survival in patients with colorectal cancer. METHODS: All patients with peritoneal metastasis from colorectal cancer who underwent CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC) between November 2008 and October 2014 were included. The growth inhibition rate was expressed as the ratio between the image density after treatment (T) and that before treatment (control, C). Tumours with a reduction in T/C ratio of less than 20 per cent were defined as resistant and those with a reduction of 20 per cent or more as sensitive. Groups were compared for overall (OS) and disease-free (DFS) survival. RESULTS: Of 84 eligible patients, 81 received neoadjuvant chemotherapy (NACT), including 56 patients with an oxaliplatin-based regimen. Mean(s.d.) follow-up was 23·4(22·9) months. The median overall survival of all patients was 19·0 (i.q.r. 5·7-36·1) months, with a progression-free survival time of 10·1 (4·5-17·0) months. Patients who received oxaliplatin-based NACT had significantly altered chemosensitivity to oxaliplatin; only 20 of 51 such patients showed chemosensitivity to oxaliplatin compared with 16 of 24 who did not undergo oxaliplatin-based NACT (P = 0·046). However, patients who showed chemoresistance to oxaliplatin had similar OS to those with chemosensitivity (18·8 versus 18·1 months; P = 0·835). The choice of HIPEC agents in patients who received oxaliplatin-based NACT did not significantly influence survival (oxaliplatin versus mitomycin C: median OS 20·6 (10·9-24·8) versus 19·0 (10·5-34·6) months, P = 0·811; DFS 6·6 (2·8-25·7) versus 9·3 (4·1-13·9) months, P = 0·191). CONCLUSION: Patients who had oxaliplatin-based NACT showed a higher rate of chemoresistance to oxaliplatin at the time of CRS and HIPEC. The impact of chemosensitivity testing on OS remains unclear and needs further investigation.

Should total gastrectomy and total colectomy be considered for selected patients with severe tumor burden of pseudomyxoma peritonei in cytoreductive surgery?

BACKGROUND: This study aims to evaluate the safety and efficacy of cytoreductive surgery (CRS) including total gastrectomy and total colectomy in selected pseudomyxoma peritonei (PMP) patients with entire stomach and colon covered by mucinous tumor. METHODS: A total of 48 patients received this extensive treatment between January 2006 and January 2014. The main focus of this study was survival after CRS as well as perioperative morbidity and mortality. RESULTS: Twenty-eight patients were male, and median age was 52.5 years. Median peritoneal cancer index was 33. Complete cytoreduction was achieved in all 48 patients, and 26 patients received hyperthermic intraperitoneal chemotherapy (HIPEC). Until last follow-up, the estimated median survival after CRS was 54.0 months (95% CI 36.5-71.6 months). The 1-, 2-, 3-, and 5-year survival rates were 91.7%, 81.3%, 70.1%, and 48.6%, respectively. Histology was significantly associated with survival (P = 0.020). The median disease-free survival was 32.0 (95% CI 25.7-38.3) months. HIPEC (P = 0.048) and histology (P = 0.002) was significantly associated with disease-free survival after CRS. Overall Grade 3-5 complications occurred in 18 (37.5%) patients with mortality of 2.1%. For patients who received surgery over 6 months, they could gradually have an acceptable quality-of-life similar as other patients receiving ordinary CRS and HIPEC. CONCLUSION: CRS including total gastrectomy and total colectomy can be performed in experienced specialized institutions as a feasible option to achieve complete cytoreduction with acceptable safety in selected PMP patients with stomach and colon covered by mucinous tumor. Perioperative management should be carried out cautiously to decrease and avoid complications.

A comprehensive treatment for peritoneal metastases from gastric cancer with curative intent.

Recently, Peritoneal Surface Oncology Group International (PSOGI) developed a novel comprehensive treatment consisting of cytoreductive surgery (CRS) and perioperative chemotherapy (POC) for the treatment of peritoneal metastases (PM) from gastric cancer with curative intent. This article reviews the results of this treatment and verifies its indication. In this strategy, peritoneal cancer index (PCI) is determined by laparoscopy, and a peritoneal port is placed. Neoadjuvant bidirectional intraperitoneal/systemic chemotherapy (NIPS) is performed for 3 cycles, and then laparotomy is performed. Cytoreductive surgery with peritonectomy procedures and hyperthermic intraperitoneal chemoperfusion (HIPEC) are performed. Multivariate analyses showed that completeness of cytoreduction, pathologic response to NIPS and PCI level and cytologic status after NIPS, as independent prognostic factors. PCI less than cut-off level after NIPS, negative cytology after NIPS, and positive response to NIPS were identified as the indications for comprehensive treatment. Patients who hold these criteria should be considered as the candidates for CRS and HIPEC.

Surgical results of patients with peritoneal carcinomatosis treated with cytoreductive surgery using a new technique named aqua dissection.

During 2004 to 2011, 81, 420, and 166 patients with colorectal cancer (CRC), epithelial appendiceal neoplasm (APN), and gastric cancer (GC) with PC were treated with cytoreductive surgery (CRS) plus perioperative chemotherapy. CRS was performed by peritonectomy techniques using an aqua dissection. Results. Complete cytoreduction was done in 62/81 (76.5%), 228/420 (54.3%), and 101/166 (60.8%) of patients with CRC, APN, and GC. The main reasons of incomplete resections were involvement of all peritoneal regions and diffuse involvement of small bowel. The incidence (64%, 302/470) of CC-0 resection after introduction of an aqua dissection was significantly higher than before (42%, 82/197). A total of 41 (6.1%) patients died postoperatively. Major complication (grade 3-4 complications) occurred in 126 patients (18.9%). A reoperation was necessary in 36 patients (5.4%). By the multivariate analysis, PCI scores capable of serving as thresholds for favorable versus poor prognosis in each group and CC scores demonstrated as the independent prognostic factors. Conclusions. Peritonectomy using an aqua dissection improves the incidence of complete cytoreduction, and improves the survival of patients with PC. Patients with PCI larger than the threshold values should be treated with chemotherapy to improve the incidences of complete cytoreduction.

Surgical treatment for peritoneal carcinomatosis from gastric cancer.

This review describes the latest surgical treatments for peritoneal carcinomatosis (PC) arising from gastric cancer. Systemic chemotherapy is less effective against PC because of the existence of the blood-peritoneal barrier. Accordingly, perioperative intraperitoneal chemotherapy plus cytoreductive surgery (CRS) is a new trend of multidisciplinary therapy for PC. Intraperitoneally administered drugs penetrate directly into the peritoneal dissemination, resulting in the high loco-regional intensity of drugs. A new bidirectional chemotherapy called neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) has been developed. After NIPS, the disappearance of PFCCs has been reported, and the incidence of complete cytoreduction has increased accordingly. Complete cytoreduction, a low peritoneal carcinomatosis index, and negative PFCCs are significant favorable prognostic factors. Hyperthermic intraperitoneal chemotherapy (HIPEC) after CRS is associated with improved survival with an acceptable postoperative mortality and morbidity. Early postoperative intraperitoneal chemotherapy (EPIC) has also contributed to improving survival after CRS.

Calcium polycarbophil, a water absorbing polymer, increases bowel movement and prevents sennoside-induced diarrhea in dogs.

The effects of calcium polycarbophil (CP), a water-absorbing polymer, on bowel movement were examined in comparison with known laxatives and anti-diarrheal agents in dogs, a species that resembles humans for stool output. CP increased stool frequency, fecal water content and fecal weight in a dose-dependent manner, but did not induce diarrhea. Sennoside and carboxymethylcellulose sodium (CMC-Na) increased fecal water content and induced diarrhea at lower doses than that which enhanced stool frequency. Trimebutine decreased stool frequency, fecal weight and fecal water content, resulting in inhibition rather than stimulation of defecation. In sennoside-induced diarrhea, loperamide and CP improved stool consistency and this was accompanied by reduced fecal moisture and frequency of diarrhea. In contrast, CMC-Na aggravated stool consistency with increased fecal water content and frequency of diarrhea, and trimebutine had little noticeable effect apart from reducing fecal weight. Our results show that CP has both laxative and anti-diarrheal effects in dogs and differed from conventional laxatives and anti-diarrheal agents. CP may be a suitable agent for treatment of idiopathic constipation, secretory diarrhea and irritable bowel syndrome with alternating constipation and diarrhea and with either predominating in terms of less side effects such as diarrhea or constipation.

Effect of truncal vagotomy on gallbladder bile kinetics in conscious dogs.

Previous studies on the effects of vagotomy on gallbladder (GB) motility have yielded conflicting results. The aim of this study was to evaluate the effects of vagotomy on GB motility and bile kinetics using a new method. Twelve dogs were divided into two groups of six (control and pyloroplasty) and, 4 weeks later, underwent truncal vagotomy. A catheter secured in the GB fundus was used to monitor GB volume. After injecting polyethylene glycol (PEG) into the GB, combined measurements of GB volume and PEG concentration enabled GB emptying and bile kinetics to be estimated. Seven and five of the 12 vagotomized dogs were classified as having large and normal fasting GB volumes, respectively. Postprandial GB emptying was impaired when the fasting GB volume was enlarged. In the fasting state, bile kinetics of vagotomized dogs were significantly smaller than the control values. The emptying ability of the GB of vagotomized dogs with large fasting GB volumes was reduced considerably both in the postprandial and the fasting states. Such retention of bile in the GB after vagotomy may facilitate cholesterol crystal nucleation and stone growth.

Postprandial normal saline intake delays gastric emptying of solids in conscious dogs: partial involvement of CCK in its mechanism.

Although it is known that a caloric liquid meal given after food intake delays solid gastric emptying, the effect of a noncaloric liquid is not known. The aims of this study were to determine the effect of normal saline given at 3 hr after feeding on gastric antral motor activity and gastric emptying and to evaluate the role of endogenous cholecystokinin in the changes in gastric function induced by postprandial saline intake in conscious dogs. Two cannulas were implanted in each of five mongrel dogs for infusion of phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum. Gastric contractile and emptying activity were measured by the force transducer method and a freeze-drying method newly developed by our group, respectively. Postprandial pancreaticobiliary secretion was assessed from amylase and bile acid outputs into the duodenum. One hundred grams of freeze-dried dog food was given as a solid meal after mixing it with 100 ml of normal saline. The dogs were given 100 ml of normal saline per os at 3 hr after feeding. In another study, intravenous administration of devazepide, a specific cholecystokinin-A receptor antagonist, at a dose of 0.1 mg/kg/hr was begun 15 min before postprandial saline intake and continued for 1 hr. Gastric antral motility was significantly (P < 0.01) inhibited for 30 min after the dogs had drunk saline at 3 hr after feeding. The mean fractional emptying rate of gastric solids in percentage per 30 min after postprandial saline intake was significantly (P < 0.05) slower than that in the control study without saline intake at 3 hr after feeding. Amylase output into the duodenum after postprandial saline intake showed a gradual increase lasting for about 1 hr, whereas that of bile acid increased transiently but markedly 15 min after saline intake, in comparison with the control study. Pretreatment with devazepide partially ameliorated the suppression of gastric antral motility. Postprandial intake of saline inhibited gastric motor activity and delayed solid gastric emptying, whereas it increased the outputs of amylase and bile acid. Endogenous cholecystokinin may be partially involved in these phenomena caused by saline intake at 3 hr after feeding.

Effect of EM574 on postprandial pancreaticobiliary secretion, gastric motor activity, and emptying in conscious dogs.

EM574, an erythromycin derivative and a potent motilin receptor agonist, is now under clinical trial as a gastroprokinetic drug. The aim of this study was to estimate the effect of EM574 on postprandial pancreaticobiliary secretion, gastric motor activity, and emptying in conscious dogs. Five mongrel dogs were prepared. Indwelling cannulas for both infusion of phenolsulfonphthalein and aspiration of luminal samples were inserted into the proximal and distal duodenum, respectively. EM574 (3-30 microg/kg) was given intraduodenally through the indwelling distal duodenal cannula at the start of feeding. Postprandial pancreatic and biliary secretions were assessed by measuring the outputs of amylase and bile acid into the duodenum, respectively. Gastric motor and emptying activity were measured by means of a force transducer method and our own freeze-drying method, respectively. One hundred grams of a freeze-dried standard meal was given as a solid marker after being mixed with 100 ml of normal saline containing 15 g of polyethylene glycol as a liquid marker. EM574 at doses of 10 and 30 microg/kg significantly increased the mean integrated postprandial amylase output into the duodenum, but the mean integrated postprandial bile acid output was not significantly increased. EM574 increased postprandial gastric antral motor activity dose-dependently. EM574 at doses of 10 and 30 microg/kg significantly accelerated gastric emptying of liquids and solids, respectively. EM574 enhances gastric antral motor activity and accelerates gastric emptying of solids and liquids with a concomitant increase in postprandial pancreatic amylase, but not bile acid, output in normal dogs.

Effect of bacterial or porcine lipase with low- or high-fat diets on nutrient absorption in pancreatic-insufficient dogs.

BACKGROUND & AIMS: Treatment of human exocrine pancreatic insufficiency is suboptimal. This study assessed the effects of bacterial lipase, porcine lipase, and diets on carbohydrate, fat, and protein absorption in pancreatic-insufficient dogs. METHODS: Dogs were given bacterial or porcine lipase and 3 diets: a 48% carbohydrate, 27% fat, and 25% protein standard diet; a high-carbohydrate, low-fat, and low-protein diet; or a low-carbohydrate, high-fat, and high-protein diet (66%/18%/16% and 21%/43%/36% calories). RESULTS: With the standard diet, coefficient of fat absorption increased dose-dependently with both lipases (P < 0.05), but more fat was absorbed with porcine lipase (P < 0.05); 600, 000 IU of bacterial lipase (240 mg) and 300,000 IU of porcine lipase (18 g) nearly abolished steatorrhea. With 300,000 IU of bacterial lipase or 135,000 IU of porcine lipase, fat absorption was greater with the high-fat and -protein diet (P < 0.05 vs. low-fat and -protein diet). There were no interactions among carbohydrate, fat, and protein absorption. CONCLUSIONS: Correcting steatorrhea requires 75 times more porcine than bacterial lipase (18 vs. 240 mg). High-fat and high-protein diets optimize fat absorption with both enzymes. High-fat diets with bacterial or porcine lipase should be evaluated in humans with pancreatic steatorrhea.

Mechanism of inhibitory effect of glucagon on gastrointestinal motility and cause of side effects of glucagon.

Glucagon is commonly used during gastrointestinal examinations for the temporary inhibition of gastroduodenal movements. Three preparations of glucagon are now clinically available: those prepared by extraction from the pancreas (GL-P), by chemical synthesis (GL-S), and by genetic recombination (GL-G). The aim of this study was examine the mechanism of the inhibitory effect of glucagon on gastrointestinal motility and the cause of its side effects by comparing three glucagon preparations. In four conscious dogs, gastrointestinal contractions were monitored by means of chronically implanted force transducers. Each glucagon preparation (GL-P [15 microg/kg], GL-S [5, 15, 45 microg/kg], GL-G [15 microg/kg]), scopolamine butylbromide (0.4 mg/ kg), or saline was administered intravenously 20 min after the termination of spontaneous phase III contractions, and blood samples were taken at 5- to 10-min intervals. Barium was administered into the stomach 10 min after the infusion of each drug. The arrival of a barium meal in the stomach immediately stimulated gastrointestinal contractions, and the barium meal was expelled into the duodenum and jejunum from the stomach. Intravenous injection of 15 microg GL-S first stimulated duodenal contractions that propagated to the jejunum, followed by strong inhibition of the barium-induced gastrointestinal contractions. This inhibitory effect of glucagon and the activity of the glucagon-induced duodenal contractions were dose-related. The inhibitory effects of GL-G and GL-S were stronger than that of GL-P. Blood glucose and plasma insulin concentrations were raised after intravenous injection of each glucagon preparation, but there was no difference among the three preparations and no dose relationship. The inhibitory effects of glucagon depend on the material purity and dose, and the inhibitory mechanism was independent of any effect on carbohydrate metabolism. Glucagon administration caused phase III-like contractions in the duodenum and jejunum, which may be responsible for the side effects of glucagon.

Effects of EM574 and cisapride on gastric contractile and emptying activity in normal and drug-induced gastroparesis in dogs.

EM574, an erythromycin derivative and potent motilin receptor agonist, is now undergoing clinical trials as a gastroprokinetic drug. The aim of this study was to compare the effect of EM574 with that of cisapride on gastric motility and emptying in normal and gastroparesis dogs. Six dogs were each implanted with two duodenal cannulas for infusion of phenolsulfonphthalein into the proximal duodenum and for aspiration of luminal samples from the distal duodenum. Both solid and liquid gastric emptying were determined by a novel freeze-drying method developed in our laboratory. A freeze-dried standard meal (100 g, 400 kcal) was given with 100 ml normal saline containing 15 g of polyethylene glycol as a liquid marker. Gastric muscle contractility was measured by means of a force transducer implanted on the gastric antrum. EM574 (3-30 microgram/kg) and cisapride (0.3-3.0 mg/kg) were administered intraduodenally at the start of feeding. Clonidine (3-30 microgram/kg) was injected subcutaneously 15 min before feeding to induce gastroparesis. EM574 and cisapride both enhanced gastric muscle contractility in a dose-dependent manner. EM574 (30 microgram/kg and 10 microgram/kg) significantly accelerated gastric emptying of solids and liquids, respectively. Cisapride (1 mg/kg) significantly accelerated solid gastric emptying, but 3.0 mg/kg significantly delayed liquid gastric emptying. Clonidine (10 and 30 microgram/kg) significantly delayed solid and liquid gastric emptying and reduced gastric muscle contractility. EM574, at a dose of 30 microgram/kg, completely restored solid and liquid gastric emptying and muscle contractility to the normal range in dogs with clonidine-induced gastroparesis. Cisapride (1 mg/kg) restored liquid gastric emptying in dogs with gastroparesis to the normal range and partially restored solid emptying. EM574 accelerated gastric muscle contractility and emptying of solids and liquids in normal dogs. The stimulating activity of EM574 on gastric muscle contractility and emptying was comparable to that of cisapride, but EM574 was as effective as cisapride in normalizing gastric muscle contractility and emptying in dogs with clonidine-induced gastroparesis.

Effect of TKS159, a novel 5-hydroxytryptamine4 agonist, on gastric contractile activity in conscious dogs.

A novel 5-hydroxytryptamine (5-HT)4 receptor agonist, TKS159, ¿4-amino-5-chloro-2-methoxy-N-[(2S,4S)-1-ethyl-2- hydroxymethyl-4-pyrrolidinyl] benzamide), has recently been developed as a gastroprokinetic drug. Cisapride is already used clinically to increase gastric contractions. The stimulatory effects of TKS159 and cisapride on gastric contractions were examined using force transducers chronically implanted on the vagally denervated pouch (Heidenhain pouch) and the vagally innervated main stomach in conscious dogs. Contractile activity was analysed by computer and expressed as a motor index. Intravenous administration of TKS159 or cisapride significantly increased the motor index in both the main stomach and the Heidenhain pouch during the fed and fasted states. Pharmacological characterization in the fasted state revealed that the contraction-stimulating activity of TKS159 and cisapride on the stomach was significantly inhibited by atropine, hexamethonium and a 5-HT4 receptor antagonist, SDZ 205-557. Granisetron (a 5-HT3 receptor antagonist) significantly inhibited cisapride-induced, but not TKS159-induced gastric contractions. The plasma motilin concentration was significantly increased after cisapride, but not after TKS159 injection. In conclusion, TKS159 has a contractile-stimulating effect on both the innervated and the denervated stomach. It is likely that a cholinergic pathway and 5-HT4 receptors are involved in producing the contractions, although other mechanisms cannot be excluded. Cisapride has almost the same characteristics, but the present findings suggest the involvement of motilin and 5-HT3 receptors in the effects of cisapride.

An evaluation of motor function in transverse colon transplants after total gastrectomy.

The motor activity of the isolated colon is understood less than that of any other part of the gastrointestinal viscus. Thus, the aim of the present study was to evaluate the motor activity of the interposed transverse colon following total gastrectomy through a study of 21 patients. Manometric studies were carried out with a 5-lumen, open-tipped catheter in the resting state, in response to dry swallows, and swallowing distilled water and a liquid meal. Contractile waves in the interposed colon grafts were divided into three types, namely, high-amplitude propagated contractions (HAPCs), low-amplitude propagated contractions (LAPCs), and low-amplitude nonpropagated contractions (LANPCs). No retrograde contractions were observed during the entire recording. Motor activity in the interposed colon increased to a greater extent after swallowing distilled water or liquid meals than during the resting period or after dry swallows; however, there was no significant difference between the effect of distilled water and liquid meals. The motor activity of the interposed colon was lower in patients with symptoms than in asymptomatic patients. These results suggest that the volume, rather than the composition, of the lumen contents is an important factor for inducing interposed colon graft contractions, and that contractions of the interposed colon can help to propel the contents of the colon into the duodenum and clear any duodenal juice if reflux should occur.

Motilin controls cyclic release of insulin through vagal cholinergic muscarinic pathways in fasted dogs.

The effect of motilin on insulin release has not been studied in the interdigestive state. Adult mongrel dogs were chronically implanted with force transducers in the stomach and duodenum to monitor contractile activity, and the plasma motilin and insulin concentrations were measured by a specific radioimmunoassay and enzyme immunoassay, respectively. The concentration of insulin in plasma was found to fluctuate in close association with that of motilin and phase III of the interdigestive migrating contractions in the stomach. This spontaneous release of insulin was mimicked by intravenous infusion of motilin at a dose of 0.3 microgram.kg-1.h-1. Exogenous motilin (0.01-0.3 microgram/kg) dose dependently stimulated insulin release, which was abolished by atropine, hexamethonium, ondansetron, and truncal vagotomy. Phentolamine significantly enhanced, whereas propranolol inhibited, motilin-induced insulin release. In a perifusion system using islet cells from the canine pancreas, motilin did not affect insulin release. In conclusion, motilin stimulates insulin release through vagal cholinergic, muscarinic receptors on pancreatic beta-cells, and the effect appears to be modulated by adrenergic nerves.

Sodium azide induces relaxation of the canine gastric body by activating a guanylate cyclase-dependent pathway.

In order to study the inhibitory mechanism by which sodium azide eliminates smooth muscle contraction in vivo and in vitro, gastrointestinal motility was monitored via chronically implanted force transducers in the stomach and duodenum of conscious dogs. Circular smooth muscle strips with myenteric plexus from the canine gastric body were used for in vitro measurement of isometric tension. In conscious dogs, sodium azide (50 micrograms kg-1, i.v.) abolished both the spontaneously occurring phase III contractions and postprandial motility. Exogenous motilin (100 ng kg-1)- and bethanechol (50 micrograms kg-1)-induced contractions were also abolished by sodium azide. In vitro, sodium azide and electrical field stimulation (EFS) caused a concentration- or frequency-dependent nonadrenergic noncholinergic relaxation in the gastric body strips. The relaxation induced by EFS, but not sodium azide, was abolished by tetrodotoxin. NG-nitro-L-arginine and oxyhaemoglobin failed to attenuate the relaxant effect of sodium azide, but strongly inhibited EFS-induced relaxation. Methylene blue inhibited both sodium azide- and EFS-induced relaxation. cGMP concentrations in muscle strips were markedly increased by sodium azide. These findings indicate that sodium azide induces relaxation in the canine gastric body through a direct action on smooth muscle, by activating a guanylate cyclase-dependent pathway; endogenous NO synthesis does not participate in this inhibitory mechanism.

Effect of nitric oxide synthase inhibition on plasma motilin release in fasted dogs.

Inhibition of nitric oxide (NO) synthase on plasma motilin concentrations is not known. The aim of this study was to examine the effect of NO synthesis inhibitor on gastrointestinal motility and motilin release in conscious dogs. Dogs fitted with force transducers were given N omega-nitro-L-arginine (L-NNA) after the termination of phase III contractions. Blood samples were taken for measurement of motilin concentrations. L-NNA induced phase III-like contractions in the stomach in the duodenum in association with a significant increase in motilin level. Atropine or hexamethonium significantly inhibited L-NNA-induced phase III-like contractions and the increase in motilin level. Atropine or hexamethonium significantly inhibited L-NNA-induced phase III-like contractions and the increase in motilin level. Ondansetron markedly inhibited gastric, but not duodenal, phase III-like contractions without affecting the increase in motilin level caused by L-NNA. Vagotomy affected neither the occurence of phase III-like contractions nor the increase in motilin level produced by L-NNA. We conclude that inhibition of NO synthesis stimulates motilin release via cholinergic pathways independent of the vagus, and induces phase III-like contractions in the stomach and duodenum. Phase III-like contractions induced by L-NNA are mediated through the activation of 5-HT, receptors.

Bacterial lipase and high-fat diets in canine exocrine pancreatic insufficiency: a new therapy of steatorrhea?

BACKGROUND & AIMS: Nutrients and properties of lipases affect survival of lipolytic activity during aboral gastrointestinal transit. Whether different doses and formulations of bacterial lipase and diets affect steatorrhea was tested in pancreatic-insufficient dogs. METHODS: A dose of 0-600,000 IU of powdered and 135,000 and 300,000 IU of liquid bacterial lipase was given with a standard meal to 5 dogs with ligated pancreatic ducts. In 4 dogs, 0 or 300,000 IU (normal 6-hour postprandial amount) of powder bacterial lipase was also given with five meals containing 850 kcal with different nutrient caloric densities (mixture design). Coefficients of fat absorption during 72-hour fecal balance studies were used to assess treatments. RESULTS: With the standard meal, powder bacterial lipase reduced steatorrhea in a dose-dependent manner (P = 0.03), and 135,000 and 300,000 IU of the liquid form decreased steatorrhea more than powder bacterial lipase (P = 0.017 and 0.057, respectively). Coefficients of fat absorption with 300,000 IU of powder bacterial lipase correlated (r2 = 0.79; P < 0.001) with increasing proportions of fat calories in diets. CONCLUSIONS: Liquid bacterial lipase decreases steatorrhea more than powder, and 300,000 IU of powder bacterial lipase ingested with high-fat meals corrects canine pancreatic steatorrhea. The combination of adequate mixing of small amounts (milligrams) of bacterial lipase and high-fat meals abolishes canine steatorrhea and may abolish human pancreatic steatorrhea.

A new method to measure gastric emptying in conscious dogs: a validity study and effects of EM523 and L-NNA.

A new method for measurement of gastric emptying without the use of radioisotope markers has been developed in dogs. A test meal was given after measurement of its freeze-dried weight, and 1-ml duodenal samples were collected through an indwelling tube at 15-min intervals, and their absolute weight was measured. The duodenum was continuously perfused with phenolsulfonphthalein to determine the recovery of each sample. Three different calorie or fat-enriched meals were administered with 100 ml saline containing polyethylene glycol as a liquid marker. The results showed that increasing the calorie load of, and adding fat to, the test meal proportionally delayed gastric emptying of the solid phase. Utilizing this method, it was found that EM523, an erythromycin derivative, accelerated the gastric emptying of solids, whereas N(omega)-nitro-L-arginine (L-NNA) markedly delayed the gastric emptying of both solids and liquids. In conclusion, this freeze-drying method is a reliable technique for measuring the gastric emptying of the solid phase in dogs.

Long-term observations of uterine contractions in nonpregnant dogs.

Uterine contractile activity in nonpregnant conscious dogs was investigated based on 2- to 6-mo-long continuous recording by means of a chronically implanted force transducer. We found that nonpregnant uterine contractile activity could be classified into six major patterns: sporadic contractions, weak and strong tonic contractions, weak and strong phasic contractions, and phasic contraction bursts. The contractile patterns during proestrus and estrus were the most active, with strong phasic and tonic contractions and phasic contraction bursts. The phasic and tonic contractions were inhibited dose-dependently by a beta 2 adrenergic agonist, ritodrine, and reproduced by an alpha 2 adrenergic agonist, clonidine. In contrast, the cholinergic inhibitors atropine and hexamethonium did not affect the spontaneous occurrence of these contractions, although bethanechol evoked uterine contractions. Oxytocin and prostaglandin F2 alpha-induced contractions were phasic during estrus, whereas they showed tonic increases with phasic contractions during proestrus, diestrus, and anestrus, and these contractions did not resemble the spontaneous contractions. In conclusion, the nonpregnant uterus contracts continuously in harmony with the estrous cycle phases, and its contractile activity is enhanced by alpha adrenergic receptors and inhibited by beta 2 adrenergic receptors.